Substituted benzodiazepines and method of use

ABSTRACT

10-Substituted amino-4,9-dihydro-4H-thieno[3,4-b]-[1,5]benzodiazepines having neuroleptic and analgesic activity.

DESCRIPTION OF THE INVENTION

This invention is concerned with compounds of the formula: ##SPC1##

Wherein R₁ and R₂ are selected from the group consisting of hydrogen,lower alkyl, lower alkoxy, halogen, nitro, trifluoromethyl, methylthio,methylsulfonyl and hydroxy; R₃ is hydrogen or lower alkyl; R is ##SPC2##

Or --N(CH₂)_(n) N(R₅), wherein R₄ is hydrogen, lower alkyl,2-hydroxyethyl, phenyl or phenylloweralkyl; n is 2 or 3 and R₅ is loweralkyl, and acid addition salts thereof. The term lower as defined aboveis intended to include those wherein the hydrocarbon group contains from1 to 4 carbon atoms. Halogen is chlorine, bromine, fluorine or iodine.

The compounds of the present invention may be prepared by the followingreaction sequence: ##SPC3##

Wherein R, R₁, R₂ and R₃ are as defined above.

The starting material, a substituted 4,9-dihydro-10H-thieno[3,4-b] [1,5]benzodiazepin-10-thione (I) is prepared from the reaction of thecorresponding 4,9-dihydro-10H-thieno[3,4-b] [1,5] benzodiazepin-10-one(described in my copending application Ser. No. 552,023 (Case No.25,618) filed Feb. 24, 1975, and phosphorus pentasulfide in a solventsuch as pyridine at reflux. This intermediate (I) is then converted tothe correspondingly substituted 10-(methylthio)-4H-thieno[3,4-b] [1,5]benzodiazepine (II) by reaction with methyl sulfate and an alkaline basein methanol. The latter reaction is carried out at from 40° to 100°C.for a period of from about 1/2 hours to 10 hours. The intermediate (II)is the converted to the corresponding 10-substitutedamino-4,9-dihydro-4H-thieno[3,4-b][1,5] benzodiazepine (III) by reactionwith the appropriate amine at reflux temperature in acid. Thetemperature of the reaction may vary from 100° to 250°C. depending uponthe amine. The reaction is heated from 10 to 120 hours.

Specific compounds included within the scope of this invention are:

10-(4-Methyl-1-piperazinyl)-4H-thieno[3,4-b] [1,5] benzodiazepine

7-Chloro-4-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[ 3,4-b] [1,5]benzodiazepine

6-Chloro-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

7-Chloro-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]-benzodiazepine

4-Methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

10-Piperidino-4H-thieno[3,4-b] [1,5] benzodiazepine

10-(1-Piperazinyl)-4H-thieno[3,4-b] [1,5] benzodiazepine

10-[4-(2-Hydroxyethyl)-1-piperazinyl]-4H-thieno[3,4-b][1,5[benzodiazepine

10-(4-Phenyl-1-piperazinyl)-4H-thieno[3,4-b] [1,5]benzodiazepine

10-(4-Benzyl-1 -piperazinyl)-4H-thieno[3,4-b] [1,5] benzodiazepine

7-chloro-10-[4-(2-hydroxyethyl)-1-piperazinyl]-4H-thieno[3,4-b][1,5]benzodiazepine

4-Methyl-10-(1-piperazinyl)-4 H-thieno[3,4-b] [1,5] benzodiazepine

10-[4-(2-Dimethylaminoethyl)-1-piperazinyl]-4H-thieno[3,4-b][1,5]benzodiazepine

5-Fluoro-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

6-Trifluoromethyl-10-(1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

6-Fluoro-4-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

7-Methoxy-10-(4-methyl-1-piperazinyl)-4H-theino[3,4-b][1,5]benzodiazepine

6,7-Dichloro-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

5-Methoxy-10-(1-piperazinyl)-4H-thieno[3,4-b] [1,5] benzodiazepine

6,7-Dimethyl-10-[4-(2-hydroxyethyl)-1-piperazinyl]-4H-thieno[3,4-b][1,5] benzpdiazepine

6,7-Dimethoxy-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

8-Chloro-10-(1-piperazinyl)-4H-thieno[3,4-b] [1,5] benzodiazepine

4-Ethyl-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b] [1,5]benzodiazepine

7-Chloro-4-propyl-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

7-Chloro-4-methyl-10-(1-piperazinyl-4H-thieno[3,4-b][1,5]benzodiazepine

7-Chloro-10-(1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

5-Chloro-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

7-Hydroxy-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

6-Hydroxy-10-(4-methyl-1 -piperazinyl)-4H-thieno[3,4-b] [1,5]benzodiazepine

10-[4-(3-Dimethylaminopropyl)-1-piperazinyl]-4H-thieno[3,4-b][1,5]benzodiazepine

7-Methylsulfonyl-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

10-(1-Piperazinyl)-4-ethyl-4H-thieno[3,4-b][1,5] benzodiazepine

4-Ethyl-10-[4-(2-hydroxyethyl)-1-piperazinyl]-4H-thieno[3,4-b][1,5]benzodiazepine

7-Nitro-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b] [1,5]benzodiazepine

6-Methylthio-10-(4-methyl-1-piperazinyl-4H-thieno[3,4-b][1,5]benzodiazepine

The compounds of the present invention are active analgesics whenmeasured by the "writhing syndrome" test for analgesic activity asdescribed by Siegmund, et al., Proc. Soc. Exp. Bio, and Med., 95, 729(1957), with modifications. This method is based upon the reduction ofthe number of writhes following the intraperitoneal injection of onemg./kg. of body weight of phenyl p-quinone in male Swiss albino miceweighing 15-25 g. The syndrome is characterized by intermittentcontractions of the abdomen, twisting abd turning of the trunk, andextension of the hind legs beginning 3 to 5 minutes after injection ofthe phenyl p-quinone. The test compounds are administered orally at theindicated dose to groups of 2 mice each, 30 minutes before injection ofthe phenyl p-quinone. The total number of writhes exhibited by eachgroup of mice is recorded for a 3 minute period commencing 15 minutesafter injection of the phenyl p-quinone. A compound is considered activeif it reduces the total number of writhes in 2 test mice from a controlvalue of approximately 30 per pair to a value of 18 or less. Table Isummarizes the results of this test on representative compounds of thisinvention.

                                      Table I                                     __________________________________________________________________________                             Dose No. of Writhes                                         Compound          (mg/Kg)                                                                            Per Pair                                        __________________________________________________________________________    10-(4-Methyl-1-piperazinyl)-4H-thieno-                                                                 6.25 4, 2                                            [3,4-b][1,5]benzodiazepine                                                    4-Methyl-10-(4-methyl-1-piperazinyl)-4H-                                                               50   0, 0                                            thieno[3,4-b][1,5]benzodiazepine                                              7-Chloro-10-(4-methyl-1-piperazinyl)-4H-                                                               1.6  1, 2                                            thieno[3,4-b][1,5]benzodiazepine diper-                                       chlorate                                                                      6-Chloro-10-(4-methyl-1-piperazinyl)-4H-                                                               6.25 7, 6                                            thieno[3,4-b][1,5]benzodiazepine                                              7-Chloro-4-methyl-10-(4-methyl-1-pipera-                                                               1.6  6, 2                                            zinyl)-4H-thieno[3,4-b][1,5]benzodiazepine                                    diperchlorate                                                                 __________________________________________________________________________

The compounds of this invention are useful for the relief of pain andinflammation in warm-blooded animals. To determine analgesic activity, amodification of the method of Randall and Selitto [Arch. Int,Pharmacodyn., 111, 409 (1957)] is used. This test measures the painthreshold of rats whose paws are made sensitive to pressure by theinjection of 0.1 ml. of a 20% aqueous suspension of brewers yeast intothe plantar surface of the left hind paw. Constantly increasing force(16 g/second) is applied to the swollen paw using an Analgesy Meter, UgoBasile. The pressure is cut off at 250 g. of force where there is noresponse (sudden struggle or vocalization). Control rats treated withstarch vehicle respond to a pressure of about 30 g. Pressure-painthresholds are always recorded 2 hours after administration of Brewers'yeast. Test compounds are administered at the same time as the yeast, atan oral dose of 200 mg/Kg. Ratios of treated (T)/control(C) reactionthresholds are calculated as estimates of analgesic efficacy (degree ofanalgesia obtainable). Test compounds are accepted as active when theyproduce a 100% elevation of pain (T/C ≧ 1.37). The results of this teston representative compounds of the present invention appear in Table II.

                  Table II                                                        ______________________________________                                        Compound                  Ratio T/C                                           ______________________________________                                        10-(4-Methyl-1-piperazinyl)-4H-                                                                         1.57                                                thieno[3,4-b][1,5]benzodiazepine                                              7-Chloro-4-methyl-10-(4-methyl-1-                                                                       1.55                                                piperazinyl)-4H-thieno[3,4-b]-                                                [1,5]benzodiazepine diperchlorate                                             ______________________________________                                    

The compounds of the present invention are physiologically active on thecentral nervous system and show high activity as anti-psychotic orneuroleptic agents. A useful test for anti-psychotic activity consistsof measuring the reduction of spontaneous motor activity in animals.

Groups of 4 rats are treated orally with the test compound dissolved orsuspended in starch vehicle at the maximum tolerated dose. At theestimated time of peak effect, the animals are placed singly into anAnimax Activity Counter and the activity of each rat is recorded over a5 minute period. The activity counts are compared to historical orparallel control valves to determine significant increased or decreasedlocomotor activity.

The compound is considered an active depressant if the counts are 50% orless of control values.

Median effective doses (MDD₅₀) (doses which decrease locomotor activityby 50%) are determined, in groups of 6 rats, for those compounds deemedactive, by a method of least-squares [D.F. Finney, Statistical Methodsin Biological Assay, Second Edition, Hofner Publishing Co., New York,456-457 (1964)]. The effective does that causes a 50% reduction in motoractivity (MDD₅₀), expressed in mg/Kg of body weight, of some typicalcompounds of this invention is set forth in Table III.

                  Table III                                                       ______________________________________                                        Compound              MDD.sub.50 (mg/Kg)                                      ______________________________________                                        10-(4-Methyl-1-piperazinyl)-4H-                                                                     6.1                                                     thieno[3,4-b][1,5]benzodiazepine                                              6-Chloro-10-(4-methyl-1-pipera-                                                                     7.7                                                     zinyl)-4H-thieno[3,4-b][1,5]benzo-                                            diazepine                                                                     7-Chloro-10-(4-methyl-1-pipera-                                                                     20                                                      zinyl)-4H-thieno[3,4-b][1,5]benzo-                                            diazepine diperchlorate                                                       7-Chloro-4-methyl-10-(4-methyl-1-                                                                   25                                                      piperazinyl)-4H-thieno[3,4-b]-                                                [1,5]benzodiazepine diperchlorate                                             4-Methyl-10-(4-methyl-1-pipera-                                                                     12                                                      zinyl)-4H-thieno[3,4-b][1,5]benzo-                                            diazepine                                                                     ______________________________________                                    

The compounds of the present invention are physiologically active on thecentral nervous system and show high activity as anti-psychotic orneuroleptic agents. A useful test for anti-psychotic activity consistsof measuring ptosis in animals.

Ptosis is defined as closure of the palpebral aperture (eyelid) greaterthan 70%. The compounds to be tested were administered orally to groupsof 10 rats each. Periodically after treatment the rats were gentlyplaced on the cage top and examined for 90 seconds for signs of ptosis.This manipulation eliminates spontaneous ptosis. The ras were thendropped from a height of about 18 inches (exteroceptive stimulation)onto the cage top to test for reversibility of ptosis. Reversible ptosisis defined as less than 70% closure of the palpebral aperture for longerthan 1 minute after the exteroceptive stimulation and is indicative ofneuroleptic activity of the drug administered. This test has beendescribed by Tedeschi, D. H., "Criteria for the Selection ofPharmacological Test Procedures Useful in the Evaluation of NeurolepticDrugs", Proceedings of the VI International Congress of the CollegiumInternationale Neuropsychopharmacologicum, pp. 145-153, (1968). Theresults of this test on representative compounds of the presentinvention appear in Table IV, wherein the dose (ED₅₀) estimated tocreate reversible ptosis in 50% of the animals is given.

                  Table IV                                                        ______________________________________                                        Compound              ED.sub.50 (mg/Kg)                                       ______________________________________                                        10-(4-Methyl-1-piperazinyl)-4H-                                                                     13                                                      thieno[3,4-b][1,5]benzodiazepine                                              7-Chloro-10-(4-methyl-1-pipera-                                                                     10                                                      zinyl)-4H-thieno[3,4-b][1,5[benzo-                                            diazepine diperchlorate                                                       6-Chloro-10-(4-methyl-1-pipera-                                                                     17                                                      zinyl)-4H-thieno[3,4-b][1,5]benzo-                                            diazepine                                                                     ______________________________________                                    

The compounds of the present invention exhibit anti-psychotic activitywhen measured by the Discrete Trial Conditioned Avoidance Test.

In this test the compounds are administered orally to male Long-Evansrats in a universal starch vehicle. The rats have been pre-conditionedto make a 70% avoidance response.

The rats are placed in individual cages and a warning tone is soundedevery 20 seconds. Each rat has the opportunity to press a bar which, ifdone within 5 seconds, prevents an electric shock through the grid floorof the cage and is termed an avoidance response.

Each rat is given 50 trials and a score of avoidance responses is kept.The drug is administered at various dose levels. Drugs exhibitinganti-psychotic activity are known to block this avoidance response.

The effective median dose (ED₅₀) which reduces avoidance response by 50%as compared to controls is estimated. The results of such a test arerecorded in Table V.

                  Table V                                                         ______________________________________                                        Compound              ED.sub.50 (mg/Kg)                                       ______________________________________                                        10-(4-Methyl-1-piperazinyl)-4H-                                                                     7                                                       thieno[3,4-b][1,5]benzodiazepine                                              4-Methyl-10-(4-methyl-1-pipera-                                                                     17                                                      zinyl)-4H-thieno[3,4-b][1,5]benzo-                                            diazepine                                                                     Chlorpromazine        9                                                       ______________________________________                                    

The active components of this invention can be used in compositions suchas tablets; the principal active ingredient is mixed with conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate, gums orsimilar materials as non-toxic pharmaceutically acceptable diluents orcarriers. The tablets or pills of the novel compositions can belaminated or otherwise compounded to provide a dosage form affording theadvantage of prolonged or delayed action or predetermined successiveaction of the enclosed medication. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of materials can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids or mixtures of polymeric acids with such materials asshellac, shellac and cetyl alcohol, cellulose acetate and the like. Aparticularly advantageous enteric coating comprises a styrene maleicacid copolymer together with known materials contributing to the entericproperties of the coating.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration include suitablyflavored emulsions with edible oils, such as, cottonseed oil, sesameoil, coconut oil, peanut oil, and the like, as well as elixirs andsimilar pharmaceutical vehicles. Sterile suspensions or solutions can beprepared for parenteral use. Isotonic preparations containing suitablepreservatives are also desirable for injection use.

The term dosage form as described herein refers to physically discreteunits suitable as unitary dosage for warm-blooded animal subject, eachunit containing a predetermined quantity of active component calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical diluent, carrier or vehicle. The dosage may varyfrom 1 to 70 mg. per kg. of warm-blooded animal per day preferably inmultiple doses. The daily dosage requirement may be form 50 to 2000 mg.The specification for the novel dosage forms of this invention areindicated by characteristics of the active component and the particulartherapeutic effect to be achieved or the limitations inherent in the artof compounding such an active component for therapeutic use inwarm-blooded animals as disclosed in this specification. Examples ofsuitable oral dosage forms in accord with this invention are tablets,capsules, pills, powder packets, granules, wafers, cachets,teaspoonfuls, dropperfuls, ampules, vials, segregated multiples of anyof the foregoing and other forms as herein described.

EXAMPLE 1 Preparation of 4,9-Dihydro-10H-thieno[3,4-b] [1,5]benzodiazepine-10-thione

A mixture of 0.76 g. of4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 1.0 g. ofphosphorus pentasulfide in 10 ml. of dry pyridine is stirred and heatedunder reflux for 4 hours. The reaction mixture is concentrated todryness and the oily residue is stirred for 18 hours with 25-30 ml. of1N sodium carbonate solution (pH 7-7.2). The solid thus obtained iscollected, washed with water and recrystallized from methanol to giveorange crystals, m.p. 210°-212°C.

In a similar fashion7-fluoro-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one istreated with phosphorus pentasulfide to give7-fluoro-4,9-dihydro-10H-thieno[3,4-b][1,5]-benzodiazepine-10-thione.

Employing the same general procedure the following starting materialsproduce the listed products:

    6-methoxy-4,9-dihydro-10H-                                                                    →                                                                         6-methoxy-4,9-dihydro-10H-                                 thieno[3,4-b][1,5]benzo-                                                                         thieno[3,4-b][1,5]benzo-                                   diazepin-10-one    diazepin-10-thione                                         7-hydroxy-4,9-dihydro-10H-                                                                    →                                                                         7-hydroxy-4,9-dihydro-10H-                                 thieno[3,4-b][1,5]benzo-                                                                         thieno[3,4-b][1,5]benzo-                                   diazepin-10-one    diazepin-10-thione                                         6-trifluoromethyl-4,9-                                                                        →                                                                         6-trifluoromethyl-4,9-                                     dihydro-10H-thieno[3,4-b]-                                                                       dihydro-10H-thieno[3,4-b]                                  [1,5]benzodiazepin-10-one                                                                        [1,5]benzodiazepin-10-thione                               5-fluoro-4,9-dihydro-10H-                                                                     →                                                                         5-fluoro-4,9-dihydro-10H-                                  thieno[3,4-b][1,5]benzo-                                                                         thieno[3,4-b][1,5]benzo-                                   diazepin-10-one    diazepin-10-thione                                         7-nitro-4,9-dihydro-10H-                                                                      →                                                                         7-nitro-4,9-dihydro-10H-                                   thieno[3,4-b][1,5]benzo-                                                                         thieno[3,4-b][1,5]benzo-                                   diazepin-10-one    diazepin-10-thione                                         6-methylthio-4,9-dihydro-                                                                     →                                                                         6-methylthio-4,9-dihydro-                                  10H-thieno[3,4-b][1,5]-                                                                          10H-thieno[3,4-b][1,5]-                                    benzodiazepin-10-one                                                                             benzodiazepin-10-thione                                    7-methylsulfonyl-4,9-                                                                         →                                                                         7-methylsulfonyl-4,9-                                      dihydro-10H-thieno[3,4-b]-                                                                       dihydro-10H-thieno[3,4-b]-                                 [1,5]benzodiazepin-10-one                                                                        [1,5]benzodiazepin-10-thione                               7-methyl-4,9-dihydro-10H-                                                                     →                                                                         7-methyl-4,9-dihydro-10H-                                  thieno[3,4-b][1,5]benzo-                                                                         thieno[3,4-b][1,5]benzo-                                   diazepin-10-one    diazepin-10-thione                                     

EXAMPLE 2 Preparation of 10-(Methylthio)-4H-thieno[3,4-b] [1,5]benzodiazepine

To a stirred suspension of 1.3 g. of 4,9-dihydro-10H-thieno[3,4-b] [1,5]benzodiazepin-10-thione in 15 ml. of dioxane is added simultaneously at<40°C., a solution of 1.9 g. of potassium hydroxide in 10 ml. ofmethanol and 2.2 g. of methyl sulfate. After addition is complete,stirring is continued for 1.5 hours. The mixture is diluted withmethanol and filtered. The filtrate is concentrated to about 20 ml.,diluted with water and filtered. The sticky precipitate is dissolved inchloroform; the chloroform solution is dried and concentrated to give asolid, which is recrystallized from methanol-water to give deep yellowcrystals, m.p. 128.5°-130°C.

In a similar manner 7-fluoro-4,9-dihydro-10H-thieno[3,4-b] [1,5]benzodiazepin-10-thione is reacted with potassium hydroxide and methylsulfate to give7-fluoro-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine.

Employing the same general procedure the following starting materialsproduce the listed products:

    6-methoxy-4,9-dihydro-10H-                                                                        6-methoxy-10-(methylthio)-                                thieno[3,4-b][1,5]benzo-                                                                      →                                                                          4H-thieno[3,4-b][1,5]-                                    diazepin-10-thione  benzodiazepine                                            7-hydroxy-4,9-dihydro-10H-                                                                        7-hydroxy-10-(methylthio)-                                thieno[3,4-b][1,5]benzo-                                                                      →                                                                          4H-thieno[3,4-b][1,5]-                                    diazepin-10-thione  benzodiazepine                                            6-trifluoromethyl-4,9-                                                                            6-trifluoromethyl-10-                                     dihydro-10H-thieno[3,4-b]-                                                                    →                                                                          (methylthio)-4H-thieno-                                   [1,5]benzodiazepin-10-                                                                            [3,4-b][1,5]benzodiazepine                                thione                                                                        5-fluoro-4,9-dihydro-10H-                                                                         5-fluoro-10-(methylthio)-                                 thieno[3,4-b][1,5]benzo-                                                                      →                                                                          4H-thieno[3,4-b][1,5]-                                    diazepin-10-thione  benzodiazepine                                            7-nitro-4,9-dihydro-10H-                                                                          7-nitro-10-(methylthio)-                                  thieno[3,4-b][1,5]benzo-                                                                      →                                                                          4H-thieno[3,4-b][1,5]-                                    diazepin-10-thione  benzodiazepine                                            6-methylthio-4,9-dihydro-                                                                         6-methylthio-10-(methyl-                                  10H-thieno[3,4-b][1,5]-                                                                       →                                                                          thio)-4H-thieno[3,4-b]-                                   benzodiazepin-10-thione                                                                           [1,5]benzodiazepine                                       7-methylsulfonyl-4,9-di-                                                                          7-methylsulfonyl-10-                                      hydro-10H-thieno[3,4-b]-                                                                      →                                                                          (methylthio)-4H-thieno-                                   [1,5]-benzodiazepin-10-                                                                           [3,4-b][1,5]benzodiazepine                                thione                                                                        7-methyl-4,9-dihydro-10H-                                                                         7-methyl-10-(methylthio)-                                 thieno[3,4-b][1,5]benzo-                                                                      →                                                                          4H-thieno[3,4-b][1,5]-                                    diazepin-10-thione  benzodiazepine                                        

EXAMPLE 3 Preparation of10-(4-Methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

A solution of 1.0 g. of10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine in 5 ml. ofN-methylpiperazine is treated with 2-3 drops of glacial acetic acid andheated under reflux for 4 days. The solution is concentrated to drynessand the residue is warmed with dilute acetic acid. The acidic solutionis filtered, cooled and made alkaline with concentrated ammoniumhydroxide. The precipitate is collected, washed with water andrecrystallized fom acetone-petroleum ether (30°-60°C.) to give yellowcrystals, m.p. 197.5°-199°C.

In a similar manner 7-fluoro-10-(methylthio)-4H-thieno[3,4-b] [1,5]benzodiazepine is reacted with N-methylpiperazine to give7-fluoro-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b] [1,5]benzodiazepine and 7-methoxy-10-(methylthio)-4H-thieno[3,4-b] [1,5]benzodiazepine gives7-methoxy-10-(4-methyl-1-piperazinyl)-4-H-thieno[3,4-b] [1,5]benzodiazepine.

EXAMPLE 4 Preparation of 10-(1-Piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

A bomb charged with 2.5 g. of 10-(methylthio)-4H-thieno[3,4-b] [1,5]benzodiazepine, 8.6 g. of piperazine, and three drops of acetic acid isplaced in an oil bath and heated at 155°-160°C. for 4 days. The bomb isthen cooled and the contents are dissolved in 2N acetic acid. Thesolution is filtered and the filtrate is made alkaline with ammoniumhydroxide and extracted with chloroform. The extracts are dried,filtered and evaporated to give a yellow solid. Recrystallization fromethanol gives the product as light tan crystals which melt at228°-231°C. (dec.).

EXAMPLE 5 Preparation of 10-(Piperidino)-4H-thieno[3,4-b] [1,5]benzodiazepine

A solution of 0.7 g. of 10-(methylthio)-4H-thieno[3,4-b] [1,5]benzodiazepine in 5 ml. of piperidine is treated with a drop of glacialacetic acid and heated under reflux for 4 days. Excess piperidine isremoved under reduce pressure and the oily residue is warmed with diluteacetic acid and filtered. The filtrate is cooled and made alkaline withconcentrated ammonium hydroxide to give a yellow solid.Recrystallization from acetone-petroleum ether (30°-60°C.) gives yellowcrystals, m.p. 157°-159°C.

EXAMPLE 6 Preparation of 4,9-Dihydro-4-methyl-10-H-thieno[3,4-b][1,5]benzodiazepin-10-thione

A mixture of 0.4 g. of 4,9-dihydro-4-methyl-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one and 0.5 g. of phosphorus pentasulfide in 5 ml. ofdry pyridine is stirred and heated under reflux for 4 hours. Thereaction mixture is concentrated to dryness and the residue is stirredwith 10 ml. of 1N sodium carbonate solution for 18 hours. Theprecipitate is collected, washed with water and recrystallized frommethanol to give gold crystals, m.p. 203°-204°C.

EXAMPLE 7 Preparation of 4-Methyl-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine

To a stirred suspension of 0.7 g. of4,9-dihydro-4-methyl-10H-thieno[3,4-b] [1,5] benzodiazepin-10-thione in10 ml. of dioxane is added dropwise and simultaneously at 30°-40°C., asolution of 0.95 g. of potassium hydroxide in 10 ml. of methanol and 0.8ml. of methyl sulfate. After addition is complete, the mixture isstirred for 3 hours, diluted with methanol and filtered. The filtrate isconcentrated to about 20 ml., diluted with water and extracted withchloroform. The chloroform solution is concentrated to give a solid,which is recrystallized from methanol-water to give orgnae crystals,m.p. 113°-115°C.

EXAMPLE 8 Preparation of4-Methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

A solution of 1.2 g. of 4-methyl-10-(methylthio)-4H-thieno[3,4-b] [1,5]benzodiazepine in 6 ml. of N-methylpiperazine is treated with 2-3 dropsof glacial acetic acid and heated under reflux for 4 days. The solutionis concentrated to dryness and the residue is warmed with dilute aceticacid. The acidic solution is filtered, cooled, and made alkaline withconcentrated ammonium hydroxide solution. The precipitate is collected,washed with water and dissolved in chloroform. The chloroform solutionis dried and concentrated to an oil, which slowly crystallizes.Recrystallization from ethanol gives yellow crystals, m.p. 83°-85°C.

EXAMPLE 9 Preparation of a mixture of6-Chloro-1,3,4,9-tetrahydro-10H-thieno[3,4-b][1,5] benzodiazepin-10-oneand 7-Chloro-1,3,4,9-tetrahydro-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one

A solution of 0.4 g. of methyl tetrahydro-4-oxo-3-thiophenecarboxylateand 0.36 g. of 4-chloro-o-phenylenediamine in 20 ml. of toluene isheated under reflux for 3 hours, cooled and filtered. The solid obtainedis recrystallized from dimethylformamide to give a yellow solid, m.p.233°-235°C. (dec.).

EXAMPLE 10 Preparation of 6-Chloro-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-one and 7-Chloro-4,9-dihydro-10H-thieno[3,4-b][1,5] benzodiazepin-10-one

To a suspension of 1.5 g. of the mixture of6-chloro-1,3,4,9-tetrahydro-10H-thieno[3,4-b] [1,5] benzodiazepin-10-oneand 7-chloro-1,3,4,9-tetrahydro-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one (prepared as described in Example 9) in 15 ml. ofdry pyridine is added, in portions, 0.8 g. of N-chlorosuccinimide. Theresulting solution is heated on a steam bath for 15-20 minutes, cooledand diluted with water. The precipitate is collected and recrystallizedfrom methanol to give deep gold crystals, m.p. 279°-281°C., with arepure 6-chloro-4,9-dihydro-10H-thieno[3,4-b] [1,5] benzodiazepin-10-one.The methanol filtrate is diluted with water to give a yellow solid, m.p.197°-198°C. which is pure 7-chloro-4,9-dihydro-10H-thieno[3,4-b] 1,5]benzodiazepin-10-one.

EXAMPLE 11 Preparation of 7-Chloro-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepin-10-thione

A mixture of 0.88 g. of 7-chloro-4,9-dihydro-10H-thieno[3,4-b] [1,5benzodiazepin-10-one and 1.0 g. of phosphorus pentasulfide in 10 ml. ofdry pyridine is stirred and heated under reflux for 4 hours. The mixtureis concentrated to dryness and the residue is stirred in 20 ml. of 1Nsodium carbonate solution (pH 7-7.2) for 18 hours. The precipitate iscollected, washed with water and recrystallized from methanol-water togive a deep yellow solid, m.p. 197°-198.5°C. (dec.).

EXAMPLE 12 Preparation of 7-Chloro-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine

To a stirred suspension of 0.8 g. of7-chloro-4,9-dihydro-10H-thieno[3,4-b] [1,5] benzodiazepine-10-thione in10 ml of dioxane is added dropwise and simultaneously at 30°-40°C., asolution of 0.95 g. of potassium hydroxide in 10 ml. of methanol and 0.8g. of methyl sulfate. After addition is complete, the reaction mixtureis stirred for 3 hours, diluted with methanol and filtered. The filtrateis concentrated to 20 ml., diluted with water and extracted withchloroform. The chloroform solution is concentrated under reducedpressure to give a solid, which is recrystallized from methanol-water togive yellow crystals, m.p. 111°-113°C.

EXAMPLE 13 Preparation of7-Chloro-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b] [1,5]benzodiazepine diperchlorate

A solution of 0.9 g. of 7-chloro-10-(methylthio)-4H-thieno[3,4-b] [1,5]benzodiazepine in 4.5 ml. of N-methylpiperazine is treated with 2-3drops of glacial acetic acid and heated under reflux for 4 days. Thesolution is concentrated to dryness and the residue is warmed withdilute acetic acid. The acidic solution is filtered, cooled and madealkaline with concentrated ammonium hydroxide. The sticky precipitate iscollected and dissolved in chloroform. The dried chloroform solution isconcentrated under reduced pressure to give7-chloro-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b] [1,5]benzodiazepine as an oil. An ethanolic solution of the oil is treatedwith 70% perchloric acid and diluted with water. The precipitate isrecrystallized from methanol to give yellow crystals, m.p. 268°-270°C.(dec.).

EXAMPLE 14 Preparation of 6-Chloro-4,9-dihydro-10H-thieno[3,4-b][1,5]benzodiazepine-10-thione

A mixture of 0.88 g. of 6-chloro-4,9-dihydro-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one and 1.0 g. of phosphorus pentasulfide in 10 ml. ofdry pyridine is stirred and heated under reflux for 4 hours. Thereaction mixture is concentrated to dryness and the residue is stirredwith 20 ml. of 1N sodium carbonate solution (pH 7-7.2) for 18 hours. Theprecipitate is collected, washed with water and recrystallized frommethanol to give an organic solid, m.p. 235°-237°C. (dec.).

EXAMPLE 15 Preparation of 6-Chloro-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine

To a stirred suspension of 0.7 g. of6-chloro-4,9-dihydro-10H-thieno[3,4-b] [1,5]benzodiazepin-10-thione in10 ml. of dioxane is added dropwise and simultaneously at 30°-40°C., asolution of 0.95 g. of potassium hydroxide in 10 ml. of methanol and 0.8g. of methylsulfate. After addition is complete, the mixture is stirredfor 3 hours, diluted with methanol and filtered. The filtrate isconcentrated to 20 ml. and diluted with water. The precipitate iscollected, washed with water and recrystallized from methanol-water togive yellow crystals, m.p. 152°-154°C.

EXAMPLE 16 Preparation of6-Chloro-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b] [1,5]benzodiazepine

A solution of 0.7 g. of 6-chloro-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine in 3.5 ml. of N-methylpiperazine is treated with 1-2drops of glacial acetic acid and heated undr reflux for 4 days. Thesolution is concentrated to dryness and the residue is warmed withdilute acetic acid. The acidic solution is filtered, cooled, and madealkaline with concentrated ammonium hydroxide. The precipitate iscollected, washed with water and recrystallized from acetone-petroleumether (30°-60°C.) to give yellow crystals, m.p. 148°-149°C. (dec.).

EXAMPLE 17 Preparation of a mixture of7-Chloro-1,3,4,9-tetrahydro-4-methyl-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one and6-Chloro-1,3,4,9-tetrahydro-9-methyl-10H-thieno[3,4-b][1,5]benzodiazepin-10-one

A solution of 2.8 g. of methyl tetrahydro-4-oxo-3-thiophenecarboxylateand 4.0 g. of 5-chloro-2-methylaminoaniline in 200 ml of toluene isheated under reflux for 3 hours, during which 100 ml. of distillate iscollected. The solution is cooled and the solid is collected andrecrystallized from ethylacetate to give a yellow solid, m.p.233°-235°C. (dec.).

EXAMPLE 18 Preparation of7-Chloro-4-methyl-4,9-dihydro-10H-thieno[3,4-b][1,5] benzodiazepin10-one

To a suspension of 0.53g. of the mixture of 7-chloro-4-methyl-1,3,4,9-tetrahydro-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one and6-chloro-9-methyl-1,3,4,9-tetrahydro-10H-thieno[3,4-b] [1,5]benzodiazepin-10-one (prepared as described in Example 17) in 5 ml. ofdry pyridine is added, in portions, 0.27 g. of N-chlorosuccinimide. Theresulting solution is heated on a steam bath for 15-20 minutes, cooled,diluted with water and filtered. The solid is recrystallized frommethanol to give a yellow solid which consists of the single isomer ofthe title, m.p. 244°-246°C. (dec.).

EXAMPLE 19 Preparation of7-Chloro-4-methyl-4,9-dihydro-10H-thieno[3,4-b][ 1,5]benzodiazepin-10-thione

A mixture of 0.5 g. of 7-chloro-4-methyl-4,9-dihydro-10H-thieno[3,4-b][1,5] benzodiazepin-10-one and 0.5 g. of phosphorus pentasulfide in 5ml. of dry pyridine is stirred and heated under reflux for 4 hours. Themixture is concentrated to dryness and is stirred with 10 ml. of 1Nsodium carbonate solution for 18 hours. The precipitate is collected,washed with water and recrystallized from methanol to give a yellowsolid, m.p. 238°-240°C.

EXAMPLE 20 Preparation of7-Chloro-4-methyl-10-(methylthio)-4H-thieno[3,4-b] [1,5] benzodiazepine

To a stirred suspension of 1.1 g. of7-chloro-4-methyl-4,9-dihydro-10H-thieno[3,4-b] [1,5]benzodiazepin-10-thione in 15 ml. of dioxane is added dropwise andsimultaneously at 30°-40°C., a solution of 1.3 g. of potassium hydroxidein 15 ml. of methanol and 1.1 g. of methyl sulfate. After addition iscomplete, the mixture is stirred for 3 hours, diluted with methanol andfiltered. The filtrate is concentrated to 20 ml., diluted with water andthe precipitate is collected. Recrystallization from methanol-watergives deep yellow crystals, m.p. 156°-158°C.

EXAMPLE 21 Preparation of7-Chloro-4-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5benzodiazepine diperchlorate

A solution of 0.7 g. of7-chloro-4-methyl-10-(methylthio)-4H-thieno[3,4-b] [1,5]benzodiazepinein 3.5 ml. of N-methylpiperazine is treated with 1-2 drops of glacialacetic acid and heated under reflux for 4 days. The solution isconcentrated to dryness and the residue is warmed with dilute aceticacid. The acidic solution is filtered, cooled and made alkaline withconcentrated ammonium hydroxide. The sticky precipitate is collected anddissolved in chloroform. The dried chloroform solution is concentratedunder reduced pressure to give an oil. An ethanolic solution of the oilis treated with 70% perchloric acid and is diluted with water. Theprecipitate is collected and recrystallized from ethanol to give a whitesolid, m.p. 212°-215°C. (dec.).

EXAMPLE 22 Preparation of7-Methylthio-10-[4-(2-hydroxyethyl)-1-piperazinyl]-4H-thieno[3,4-b][1,5]benzodiazepine

A solution of 7,10-bis(methylthio)-4H-thieno-[3,4-b][1,5]benzodiazepinein excess N-(2-hydroxyethyl)-piperazine and glacial acetic acid isheated at 140°-160°C. for 2 days. The solution is poured into water andthe product is collected.

EXAMPLE 23 Preparation of6-Nitro-10-(4-benzyl-1-piperazinyl)-4H-thieno[3,4-b] [1,5]benzodiazepine

A solution of 6-nitro 10-(methylthio)-4H-thieno [3,4-b] [1,5]benzodiazepine in excess N-benzylpiperazine and glacial acetic acid isheated at 140°-160°C. for 2 days. The solution is poured into water andthe product is collected.

EXAMPLE 24 Preparation of7-Hydroxy-10-(4-phenyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

A solution of7-hydroxy-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine in excessN-phenylpiperazine and glacial acetic acid is heated at 140°-160°C. for2 days. The solution is poured into water and the product is collected.

EXAMPLE 25 Preparation of7-Trifluoromethyl-10-[4-(2-dimethylaminoethyl)-1-piperazinyl]-4H-thieno[3,4-b][1,5]benzodiazepine

A solution of7-trifluoromethyl-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine inexcess 2-dimethylaminoethylamine and glacial acetic acid is heated at140°-160°C. for 2 days. The solution is poured into water and theproduct is collected.

EXAMPLE 26 Preparation of6-Methylsulfonyl-10-(1-piperazinyl)-4H-thieno[3,4-b][1,5-benzodiazepine

A solution of6-methylsulfonyl-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine inexcess piperazine and glacial acetic acid is heated in a bomb at 150°C.for 2 days. The solution is poured into water and the product iscollected.

EXAMPLE 27 Preparation of6-Methoxy-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

A solution of6-methoxy-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine in excessN-methylpiperazine and glacial acetic acid is heated at reflux for 2days. The solution is poured into water and the product is collected.

EXAMPLE 28 Preparation of7-Methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine

A solution of7-methyl-10-(methylthio)-4H-thieno[3,4-b][1,5]benzodiazepine in excessN-methylpiperazine and glacial acetic acid is heated at reflux for 2days. The solution is poured into water and the product is collected.

I claim:
 1. A compound selected from those of the formula:##SPC4##wherein R₁ and R.sub. 2 are selected from the group consistingof hydrogen, lower alkyl, lower alkoxy, halogen, nitro, trifluoromethyl,methylthio, methylsulfonyl and hydroxy; R₃ is selected from the groupconsisting of hydrogen and lower alkyl; R is selected from the groupconsisting ##SPC5## and --N(CH₂)_(n) N(R₅)₂, wherein R₄ is selected fromthe group consisting of hydrogen, lower alkyl, 2-hydroxyethyl, phenyland phenylloweralkyl, n is 2 or 3 and R₅ is lower alkyl, and acidaddition salts thereof.
 2. The compound in accordance with claim 1,10-(1-piperazinyl)-4H-thieno[3,4-b] [1,5]benzodiazepine.
 3. The compoundin accordance with claim 1, 10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine.
 4. The compound in accordance with claim 1,4-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine.
 5. The compound in accordance with claim 1,7-chloro-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine.
 6. The compound in accordance with claim 1,6-chloro-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine.
 7. The compound in accordance with claim 1,7-chloro-4-methyl-10-(4-methyl-1-piperazinyl)-4H-thieno[3,4-b][1,5]benzodiazepine.
 8. The compound in accordance with claim 1,10-piperidino-4H-thieno[3,4-b] [1,5]benzodiazepine.